title: Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer's disease.
abstract: Impaired degradation of amyloid beta (Abeta) peptides could lead to Abeta accumulation, an early trigger of Alzheimer's disease (AD). How Abeta-degrading enzymes are regulated remains largely unknown. Cystatin C (CysC, CST3) is an endogenous inhibitor of cysteine proteases, including cathepsin B (CatB), a recently discovered Abeta-degrading enzyme. A CST3 polymorphism is associated with an increased risk of late-onset sporadic AD. Here, we identified CysC as the key inhibitor of CatB-induced Abeta degradation in vivo. Genetic ablation of CST3 in hAPP-J20 mice significantly lowered soluble Abeta levels, the relative abundance of Abeta1-42, and plaque load. CysC removal also attenuated Abeta-associated cognitive deficits and behavioral abnormalities and restored synaptic plasticity in the hippocampus. Importantly, the beneficial effects of CysC reduction were abolished on a CatB null background, providing direct evidence that CysC regulates soluble Abeta and Abeta-associated neuronal deficits through inhibiting CatB-induced Abeta degradation.
authors.affiliation: Gladstone Institute of Neurological Disease, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: Binggui
authors.initials: B
authors.lastname: Sun
authors.forename: Yungui
authors.initials: Y
authors.lastname: Zhou
authors.forename: Brian
authors.initials: B
authors.lastname: Halabisky
authors.forename: Iris
authors.initials: I
authors.lastname: Lo
authors.forename: Seo-Hyun
authors.initials: SH
authors.lastname: Cho
authors.forename: Sarah
authors.initials: S
authors.lastname: Mueller-Steiner
authors.forename: Nino
authors.initials: N
authors.lastname: Devidze
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Anders
authors.initials: A
authors.lastname: Grubb
authors.forename: Li
authors.initials: L
authors.lastname: Gan
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002401:Cathepsin B / Q000378:metabolism*; D055316:Cystatin C / Q000235:genetics* / Q000378:metabolism*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011110:Polymorphism, Genetic / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D055316:Cystatin C; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D002401:Cathepsin B